Molecular modelling of the human cytochrome P450 isoform CYP2A6 and investigations of CYP2A substrate selectivity

被引：45

作者：

Lewis, DFV ^{[1
]}

Dickens, M

Lake, BG

Eddershaw, PJ

Tarbit, MH

Goldfarb, PS

机构：

[1] Univ Surrey, Sch Biol Sci, Guildford GU2 5XH, Surrey, England

[2] Glaxo Wellcome Res & Dev Ltd, Ware SG12 0DP, Herts, England

[3] BIBRA Int, Carshalton SM5 4DS, Surrey, England

来源：

TOXICOLOGY | 1999年 / 133卷 / 01期

关键词：

coumarin; 7-hydroxylase; CYP2A6; molecular modelling; substrate selectivity;

D O I：

10.1016/S0300-483X(98)00149-8

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

(1) The generation of a homology model of CYP2A6, the major catalyst of human hepatic coumarin 7-hydroxylase activity, involves the use of the recently published substrate-bound CYP102 crystal structure as a template. (2) A substantial number of structurally diverse CYP2A6 substrates are found to dock satisfactorily within the putative active site of the enzyme, leading to the formulation of a structural template (or pharmacophore) for CYP2A6 specificity/selectivity. (3) The CYP2A6 model is consistent with available evidence from site-directed mutagenesis studies carried out on CYP2A subfamily isoforms, and enables some explanation of species differences in CYP2A-mediated metabolism of certain substrates. (4) Quantitative structure-activity relationship (QSAR) analysis of CYP2A5 (the mouse orthologue) mutants yields statistically significant correlations between various properties of amino acid residues and coumarin 7-hydroxylase activity. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.

引用

页码：1 / 33

页数：33

共 80 条

[71]

Spracklin DK, 1996, DRUG METAB DISPOS, V24, P976

[72]

SQUIRES EJ, 1988, J BIOL CHEM, V263, P4166

[73] METABOLISM OF COUMARIN AND 7-ETHOXYCOUMARIN BY RAT, MOUSE, GUINEA-PIG, CYNOMOLGUS MONKEY AND HUMAN PRECISION-CUT LIVER SLICES [J].

STEENSMA, A ;

BEAMAND, JA ;

WALTERS, DG ;

PRICE, RJ ;

LAKE, BG .

XENOBIOTICA, 1994, 24 (09) :893-907

[74]

Torchin CD, 1996, DRUG METAB DISPOS, V24, P1002

[75] SEX AND STRAIN DIFFERENCES IN MOUSE HEPATIC-MICROSOMAL COUMARIN 7-HYDROXYLASE ACTIVITY [J].

VANIERSEL, M ;

WALTERS, DG ;

PRICE, PJ ;

LOVELL, DP ;

LAKE, BG .

FOOD AND CHEMICAL TOXICOLOGY, 1994, 32 (04) :387-390

[76] METABOLISM OF [3-C-14] COUMARIN BY HUMAN LIVER-MICROSOMES [J].

VANIERSEL, MLPS ;

HENDERSON, CJ ;

WALTERS, DG ;

PRICE, RJ ;

WOLF, CR ;

LAKE, BG .

XENOBIOTICA, 1994, 24 (08) :795-803

[77]

WLTER BA, 1994, P 6 N AM ISSX M RAYL, V6

[78] THE CYP2A3-GENE PRODUCT CATALYZES COUMARIN 7-HYDROXYLATION IN HUMAN LIVER-MICROSOMES [J].

YAMANO, S ;

TATSUNO, J ;

GONZALEZ, FJ .

BIOCHEMISTRY, 1990, 29 (05) :1322-1329

[79] CYTOCHROME P450 2E1 AND 2A6 ENZYMES AS MAJOR CATALYSTS FOR METABOLIC-ACTIVATION OF N-NITROSODIALKYLAMINES AND TOBACCO-RELATED NITROSAMINES IN HUMAN LIVER-MICROSOMES [J].

YAMAZAKI, H ;

INUI, Y ;

YUN, CH ;

GUENGERICH, FP ;

SHIMADA, T .

CARCINOGENESIS, 1992, 13 (10) :1789-1794

[80] Genetic polymorphism of drug metabolizing enzymes:: New mutations in CYP2D6 and CYP2A6 genes in Japanese [J].

Yokoi, T ;

Kamataki, T .

PHARMACEUTICAL RESEARCH, 1998, 15 (04) :517-524

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